While much attention has been paid to changes in transcription, the regulation of protein synthesis has only recently been recognized as an important contributor to nociceptive plasticity (Price and Geranton, 2009). Control of gene expression at the level of translation affords DRG neurons a rapid and local mechanism through which to generate new proteins involved in the amplification of nociceptive signaling. We hypothesize that algogenic compounds engage signaling to the translational machinery in nociceptors and their axons to enhance the efficiency of the rate-limiting step of translation, elongation initiation. This would lead to the rapid, de-novo synthesis of proteins that can mediate acute sensitization and act as positive retrograde signals to elicit long-lasting changes in gene expression sustaining sensitization. Our preliminary findings indicate that the pro-nociceptive cytokine, interleukin 6 (IL-6), stimulates translation-mediated changes in gene expression in DRG neurons via activation of the ERK-MNK pathway which phosphorylates and activates the eIF4E elongation initiation complex. We also show that IL-6 leads to CREB protein synthesis via this pathway suggesting that this transcription factor may act as a positive retrograde signal to the cell body linking local IL-6 effects in the periphery to transcriptional changes in the nucleus sustaining long- term sensitization of these neurons. In this proposal we will address the following questions through our specific aims: 1) How does IL-6 signal to the translation machinery in DRG neurons? 2) Does IL-6 stimulate translation within the axonal compartment to generate retrograde signaling to the neuronal nucleus? 3) What is the role of IL-6-mediated translation control in IL-6-induced acute and latent nociceptor sensitization in vivo? The proposed research will provide essential information on mechanisms of IL-6-induced translation regulation in DRG neurons and their axons leading to nociceptor sensitization, potentially unveiling new mechanisms and new targets for the management of chronic pain.

Public Health Relevance

Chronic pain is a major clinical problem with significant barriers to treatment. Changes in gene expression upon injury or disease are known causes for the chronification of pain but mechanisms underlying these effects are poorly understood. Through this research, we intend to discover novel mechanisms of regulation of gene expression, linked to translation control, which will enhance our understanding of how pain becomes chronic and potentially lead to the discovery of novel treatment avenues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065926-04
Application #
8436244
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Chen, Daofen
Project Start
2010-03-15
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$369,047
Indirect Cost
$123,225
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Megat, Salim; Shiers, Stephanie; Moy, Jamie K et al. (2018) A Critical Role for Dopamine D5 Receptors in Pain Chronicity in Male Mice. J Neurosci 38:379-397
Black, Bryan J; Atmaramani, Rahul; Kumaraju, Rajeshwari et al. (2018) Adult mouse sensory neurons on microelectrode arrays exhibit increased spontaneous and stimulus-evoked activity in the presence of interleukin-6. J Neurophysiol 120:1374-1385
Shepherd, Andrew J; Copits, Bryan A; Mickle, Aaron D et al. (2018) Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain. J Neurosci 38:7032-7057
Paige, Candler; Maruthy, Gayathri Batchalli; Mejia, Galo et al. (2018) Spinal Inhibition of P2XR or p38 Signaling Disrupts Hyperalgesic Priming in Male, but not Female, Mice. Neuroscience 385:133-142
Hassler, Shayne N; Ahmad, Fatima B; Burgos-Vega, Carolina C et al. (2018) Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice. Cephalalgia :333102418779548
Uttam, Sonali; Wong, Calvin; Price, Theodore J et al. (2018) eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity. Front Genet 9:470
Khoutorsky, Arkady; Price, Theodore J (2018) Translational Control Mechanisms in Persistent Pain. Trends Neurosci 41:100-114
Barragán-Iglesias, Paulino; Lou, Tzu-Fang; Bhat, Vandita D et al. (2018) Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice. Nat Commun 9:10
Megat, Salim; Price, Theodore J (2018) Therapeutic opportunities for pain medicines via targeting of specific translation signaling mechanisms. Neurobiol Pain 4:8-19
Moy, Jamie K; Kuhn, Jasper L; Szabo-Pardi, Thomas A et al. (2018) eIF4E phosphorylation regulates ongoing pain, independently of inflammation, and hyperalgesic priming in the mouse CFA model. Neurobiol Pain 4:45-50

Showing the most recent 10 out of 72 publications